Masaki Naohiko, Sugiyama Masaya, Shimada Noritomo, Tanaka Yasuhito, Nakamuta Makoto, Izumi Namiki, Watanabe Sumio, Tsubota Akihito, Komatsu Masafumi, Masaki Tsutomu, Enomoto Nobuyuki, Yoneda Masashi, Murata Kazumoto, Ito Kiyoaki, Koike Kazuhiko, Mizokami Masashi
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan.
J Gastroenterol Hepatol. 2014 Dec;29(12):1996-2005. doi: 10.1111/jgh.12646.
The accuracy for predicting virological outcomes of peginterferon-α and ribavirin therapy in patients with chronic hepatitis C is limited to approximately 80%, even with IL28B genotyping. Our in vitro study revealed that the numbers of (TA) dinucleotide repeats [(TA)n] of rs72258881, which is located in the promoter region of IL28B gene, might regulate IL28B transcription. We aimed to evaluate the usefulness of these host factors for predicting virological outcomes of this therapy in response-guided clinical settings.
A nationwide, multi-center prospective study in Japan determined IL28B (rs8099917) genotype, (TA)n of rs72258881, and amino acid substitutions of hepatitis C virus and used these for multivariate analysis together with other parameters at pretreatment.
After enrolling 215 patients with genotype 1 and high viral load from 23 hospitals between October 2009 and February 2011, intent-to-treat analysis identified 202 patients in whom the final virological outcomes could be determined. Non-virological response by non-TT genotype was predicted with 79.7% accuracy. When combined with the (TA)n, the incidences of virological response tended to be higher in the longer (TA)n group, regardless of rs8099917 genotype. Multivariate logistic regression analysis revealed that rs8099917 non-TT genotype (P < 0.001), shorter (TA)n (P = 0.011), mutation of amino acid 70 in the virus core region (P = 0.029), and lower levels of serum albumin (P = 0.036) were independently associated with non-virological response.
IL28B genotype and (TA)n of rs72258881 may independently affect virological outcomes of peginterferon-α and ribavirin as host factors, even in response-guided therapy.
即便进行了IL28B基因分型，聚乙二醇干扰素-α联合利巴韦林治疗慢性丙型肝炎患者时，预测病毒学转归的准确率也仅约为80%。我们的体外研究显示，位于IL28B基因启动子区域的rs72258881的（TA）二核苷酸重复序列[（TA）n]数量可能调控IL28B转录。我们旨在评估这些宿主因素在应答导向的临床环境中预测该治疗病毒学转归的实用性。
在日本开展的一项全国性、多中心前瞻性研究确定了IL28B（rs8099917）基因型、rs72258881的（TA）n以及丙型肝炎病毒的氨基酸替代情况，并将这些与治疗前的其他参数一起用于多因素分析。
2009年10月至2011年2月期间，从23家医院纳入了215例基因1型且病毒载量高的患者，意向性分析确定了202例可确定最终病毒学转归的患者。非TT基因型的非病毒学应答预测准确率为79.7%。当与（TA）n结合时，无论rs8099917基因型如何，（TA）n较长组的病毒学应答发生率往往更高。多因素logistic回归分析显示，rs8099917非TT基因型（P＜0.001）、较短的（TA）n（P = 0.011）、病毒核心区域氨基酸70突变（P = 0.029）以及血清白蛋白水平较低（P = 0.036）与非病毒学应答独立相关。
即便在应答导向治疗中，IL28B基因型和rs72258881的（TA）n作为宿主因素可能独立影响聚乙二醇干扰素-α联合利巴韦林的病毒学转归。
